| 1. |
- Attarha, Sanaz, et al.
(författare)
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Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation
- 2017
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 37, s. 81-92
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) heterogeneity is the main obstacle to efficient treatment due to the existence of sub population of cells with increased tumorigenicity and network of tumor associated parenchymal cells in the tumor microenvironment. We previously demonstrated that mast cells (MCs) infiltrate mouse and human gliomas in response to variety of signals in a glioma grade-dependent manner. However, the role of MCs in glioma development and the mechanisms behind MCs-glioma cells interaction remain unidentified. In the present study, we show that MCs upon activation by glioma cells produce soluble factors including IL-6, which are documented to be involved in cancer-related activities. We observe 'tumor educated' MCs decrease glioma cell proliferation and migration, reduce self-renewal capacity and expression of stemness markers but in turn promote glioma cell differentiation. 'Tumor educated' MC derived mediators exert these effects via inactivation of STAT3 signaling pathway through GSK3 beta down-regulation. We identified 'tumor educated' MC derived IL-6 as one of the contributors among the complex mixture of MCs mediators, to be partially involved in the observed MC induced biological effect on glioma cells. Thus, MC mediated abolition of STAT3 signaling hampers glioma cell proliferation and migration by suppressing their stemness and inducing differentiation via down-regulation of GSK3 beta expression. Targeting newly identified inflammatory MC-STAT3 axis could contribute to patient tailored therapy and unveil potential future therapeutic opportunities for patients.
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| 2. |
- Attarha, Sanaz
(författare)
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Search for markers and molecular mechanisms of aggressive endometrial cancer : profiling of aggressive vs non-aggressive endometrial cancers
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Endometrial cancer is the seventh frequent type of cancer among women. Identification of new prognostic markers is important to optimize treatment and follow-up of all EC patients. Understanding the molecular mechanisms of carcinogenesis may pave through discovery of further EC molecular markers. Cohort studies often disregard the individual features of tumors. Since such features may represent an opportunity to individualize cancer treatment, an innovative approach for their assessment should be developed. In this study (paper I), we addresses the previously overlooked individual characteristics of endometrial cancers, which could serve as a wellspring of information regarding specific molecular processes; regulators of such processes could potentially be useful for predicting aggression in individual endometrial tumors. Systemic analysis of individual proteome profiles represented that different proteins may be impacted in the individual endometrial tumors of different patients, but the impact of these proteins on basic cell functions may still be similar. The correlation between publically available gene expression data sets of profiling of endometrial tumors and our proteome profiling supports the conclusion that individual tumor features are doubtlessly crucial in endometrial tumorigenesis and are not inconsistent individual variations. IHC validation using tissue microarray analysis of MST1 and PKN1 proteins suggested their potential to serve as predictive biomarkers for endometrial cancer as well as efficacy of this approach. Transforming growth factor-β (TGFβ) and epidermal growth factor (EGF) are two potent regulators of tumorigenesis. Signaling cross-talk between TGFβ and EGF involves a number of regulators which define the impact on cell physiology (Paper II and III). In paper II, we discuss mammalian sterile-like 1 kinase (MST1) as a negative regulator of combined TGFβ and EGF signaling. We observed that enhanced expression of MST1 inhibited the combined action of TGFβ1 and EGF on cell invasiveness, migration and proliferation. Monitoring of the intracellular regulatory proteins showed that the MST1 contribution to TGFβ-EGF cross-talk may involve focal adhesion kinase and E-cadherin, but not activation of Smad2. Our data elucidated the negative feedback role of MST1 on TGFβ1‑ and EGF-regulated cell invasiveness, migration and proliferation. Our results from paper III demonstrated that protein kinase N1 (PKN1) modulated responses of HEC-A-1 endometrial cancer cells to TGFβ1 and EGF. PKN1 had an inhibitory effect on stimulation of cell migration, and PKN1 kinase activity was required for the inhibitory effect of TGFβ and EGF on cell proliferation and invasiveness. We observed that phosphorylation of Smad2, FAK and Erk1/2 correlated with cellular response to TGFβ1 and EGF. PKN1 modulates TGFβ and EGF-dependent regulation of cell proliferation, migration and invasiveness, and is therefore a component of the signaling network downstream of TGFβ and EGF. Thus, our findings provided insights into different mechanisms of tumorigenesis and on the impact of cross-talk between signaling pathways on tumor development
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| 3. |
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| 4. |
- Govorov, Igor, et al.
(författare)
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STK4 protein expression pattern follows different trends in endometrioid and serous endometrial adenocarcinoma upon tumor progression
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- In a previous study, we showed that serine/threonine-protein kinase 4 (STK4) is involved in the control on proliferation and migration of endometrial cancer (EC) cells in vitro. In the present paper, we studied STK4 expression in EC tissues from a large cohort of patients to determine whether STK4 can serve as a marker for the aggressiveness and prognosis of EC. Tissue samples from patients with EC were examined for tumor type, grade, and stage. The STK4 protein expression in EC cells was assessed by immunohistochemistry and related to clinicopathological data of patients, such as progression and patient survival rate. The STK4 mRNA levels and its relation to the survival rate were analyzed also in publicly available databases. The STK4 gene expression was low at both, the mRNA and protein levels in EC, especially in serous tumors. Comparison of STK4 expression with the patient survival rate shows that the higher expression is associated with worse prognosis in serous EC, while no such dependence was found in endometrioid EC. Hence, the determination of the SKT4 expression pattern could be used as a putative prognostic marker for serous EC.
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| 5. |
- Govorov, Igor, et al.
(författare)
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Upregulation of PKN1 as a Prognosis Biomarker for Endometrial Cancer
- 2022
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Ingår i: Cancer Control. - : Sage Publications. - 1073-2748 .- 1526-2359. ; 29
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several markers of survival among endometrial cancer (EC) patients have been proposed, namely, the oncoprotein stathmin, RAF kinase inhibitor (RKIP), Cyclin A, GATA-binding protein 3 (GATA3), and growth and differentiation factor-15 (GDF-15). Their elevated expression correlated significantly with a high stage, serous papillary/clear cell subtypes, and aneuploidy. In a previous study, we reported the elevated expression of the serine/threonine protein kinase N1 (PKN1) in cancerous cells. In the present paper, we studied PKN1 expression in EC tissues from a large cohort of patients, to determine whether PKN1 can serve as a marker for the aggressiveness and prognosis of EC, and/or as a marker of survival among EC patients.METHODS: Tissue samples from EC patients were examined retrospectively for tumor type, tumor size, FIGO stage and grade, depth of invasion in the myometrium, and presence of lymph node metastasis. The PKN1 protein expression in EC cells was assessed by immunohistochemistry. PKN1 mRNA levels were analyzed in publicly available databases, using bioinformatic tools.RESULTS: We found that expression of PKN1 at the mRNA and proteins levels tended to increase in high-grade EC samples (P = .0001 and P = .06, respectively). In addition, patients with metastatic disease had higher PKN1 mRNA levels (P = .02). Moreover, patients with high PKN1 expression could be characterized by poorer survival.CONCLUSIONS: We have shown a trend of the higher PKN1 expression levels in EC patients with poor prognosis. Therefore, PKN1 might be considered as a candidate prognostic marker for EC.
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| 6. |
- Roy, Ananya, et al.
(författare)
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Serglycin as a potential biomarker for glioma : association of serglycin expression, extent of mast cell recruitment and glioblastoma progression
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:15, s. 24815-24827
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Tidskriftsartikel (refereegranskat)abstract
- Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin.In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.
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| 7. |
- Ujvari, Dorina, et al.
(författare)
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Prokineticin 1 is up-regulated by insulin in decidualizing human endometrial stromal cells
- 2018
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Ingår i: Journal of Cellular and Molecular Medicine (Print). - : WILEY. - 1582-1838 .- 1582-4934. ; 22:1, s. 163-172
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Tidskriftsartikel (refereegranskat)abstract
- Prokineticin 1 (PROK1), a hypoxia-regulated angiogenic factor, has emerged as a crucial regulator of embryo implantation and placentation. Dysregulation of PROK1 has been linked to recurrent pregnancy loss, pre-eclampsia, foetal growth restriction and preterm birth. These pregnancy complications are common in women with obesity and polycystic ovary syndrome, i.e. conditions associated with insulin resistance and compensatory hyperinsulinaemia. We investigated the effect of insulin on PROK1 expression during in vitro decidualization. Endometrial stromal cells were isolated from six healthy, regularly menstruating women and decidualized in vitro. Insulin induced a significant dose-dependent up-regulation of PROK1 on both mRNA and protein level in decidualizing endometrial stromal cells. This up-regulation was mediated by hypoxia-inducible factor 1-alpha (HIF1 alpha) via the phosphatidylinositol 3-kinase (PI3K) pathway. Furthermore, we demonstrated that PROK1 did not affect the viability, but significantly inhibited the migration of endometrial stromal cells and the migratory and invasive capacity of trophoblast cell lines. This in vitro study provides new insights into the regulation of PROK1 by insulin in human decidualizing endometrial stromal cells, the action of PROK1 on migration of endometrial stromal cells, as well as migration and invasion of trophoblasts. We speculate that hyperinsulinaemia may be involved in the mechanisms by which PROK1 is linked to placenta-related pregnancy complications.
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